Covering the World of Communication Sciences and Disorders

In Search of Stuttering's Genetic Code

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Stuttering (or stammering) has existed from the time spoken communication developed. It has been largely misunderstood and historically disregarded as a psychological or social condition, and people who stutter have fought to overcome perceptions of flawed character or ineptitude, as speech-language pathologists have sought ways to help their clients who stutter. Last year's Oscar-winning movie "The King's Speech" did much to shatter those common misconceptions and shed an insider's light onto this debilitating condition. Alongside this new publicity, scientists work hard to uncover the underlying reasons. Although researchers often have suggested that stuttering was a result of a person's inner psychology and environment, a growing number of studies indicate there is a solid genetic connection.

NIH researcher Dennis Drayna

Dennis Drayna, researcher at the National Institute on Deafness and Other Communication Disorders (NIDCD), has conducted research that has identified two genetic mutations for stuttering on chromosomes 3 and 12. He and his team have studied families in which many individuals stutter and have found that such genetic-linkage studies can identify the location of the gene or genes responsible for stuttering in these families. They have enrolled a large group of families in Pakistan, where marriages between cousins are common. Each of these families has multiple cases of stuttering, and the teams' studies identified a major linkage signal on chromosome 12. Additional studies focused on this region of chromosome 12 have identified candidate genes that may underlie stuttering in these families.

Drayna and his team also identified a series of large, English-speaking families in Cameroon, West Africa, in which persistent stuttering occurs in approximately half of the family members. Linkage studies in these families are yielding promising results, and indicate the location of distinct genes that are causative of stuttering in these families.

The ASHA Leader had an opportunity to speak with Drayna in his lab to discuss not only his research, but his passion for trying to uncover the mysteries of stuttering and his hopes that it will lead to early identification of stuttering in the future.

What are the roles of environment and genetic predisposition in the manifestation of stuttering?

This is the age-old question of nature vs. nurture. There are several experimental strategies we have developed—there are twin studies, adoption studies, and studies of large, extended families. Although currently we are working on studies of extended families, the twin studies are very powerful. I have worked on twin studies, and I should also mention I have grown twin sons (see sidebar). The most powerful [studies] are identical twins reared apart, but such twins are obviously very hard to find, so most twin studies are performed with identical twins reared together. Well-designed twin studies allow us to measure the heritability of a genetic condition (that is, the contribution of genes) versus the contribution of environmental factors.

Unlike fraternal twins, who are simply age-matched siblings, identical twins are genetic clones of each other. If there is a condition that is 100% genetic, identical twins will both have the condition. If it's something that's not 100% genetic, and something else is also at play, identical twins may or may not both have it. There have been seven twin studies about stuttering; one from Italy, one from Japan, one from Denmark, one from Finland, several from Australia, and one from the United States—different languages, different researchers, and done over the course of 40 years. Every one of these says there is a genetic component to stuttering. Every one of them. And, as the analytical methods have become more sophisticated, the heritability estimate keeps going up. In the latest study, the heritability of stuttering is 80%, which is extremely high. But it's still not 100%, so something else is likely going on. The environment is only one other possible factor—but there are also random anomalies.

Does your research work to differentiate between cases of stuttering that will resolve and those cases that will persist?

Personally, this question of persistence versus recovery is the most interesting scientific question, but geneticists can't really address it well. In our lab we study only persistent stuttering. The stuttering that resolves, just resolves. Sure it's hair-raising for us parents, but it goes away. We study the cases where it doesn't go away and affects a person for their entire life. We study familial persistent developmental stuttering because that's where we, as geneticists, can make inroads.

How do researchers establish a link between a gene mutation and a behavior trait like stuttering?

We've used the traditional method that is used for classic Mendelian disorders, but with a twist. A linkage study follows the inheritance of a disorder in families by looking for coinheritance of the disorder within a family with a genetic marker that exists at a particular place on a particular chromosome. Current instruments measure about 6,000 such marker variants across all the chromosomes. So you have variants at known locations and you assay these in families.

Most of the time, of course, nothing is inherited with a particular marker. In fact, that's one of Mendel's two laws—the law of independent assortment. Remember the garden pea studies? If you breed a tall pea plant with green seeds and a short pea plant with yellow seeds, you get all combinations: tall and green, tall and yellow, short and green, and short and yellow. But once in a while, tall always goes with green and short always goes with yellow. This is called linkage and that's what we look for in our studies. Of these 6,000 markers we test, most of them just segregate independently as they are passed from parent to offspring. But once in a while (and this is usually followed by the opening of champagne) your marker always goes with the disease you are following in the family.

In the Pakistani families we are studying, for example, there's linkage of stuttering to markers on chromosome 3, which tells us that there's a gene on chromosome 3 that causes stuttering in that particular family. The next step is to do what we call a house-to-house search. That region on chromosome 3 has 30 to 40 genes on it, so you have to start looking at all these genes to find the one that has some mutation on it. It's a lot of work.

Do you think all people who stutter do so because of genetics?

Clearly, no. Of the people who present themselves for stuttering therapy, about half have a family history of stuttering disorder. So we think perhaps half of stuttering is due to genetic factors. But there are a lot of people who stutter out there who don't self-report, nor do they remember even if they have a family history, so genetics could be at work in more than half. As for differing treatments between people who stutter for genetic reasons vs. other reasons, we don't know if different treatments are better for the former or for the latter. But as we learn more we can design experiments that can answer that.

How will this body of research help pinpoint children for whom stuttering will likely persist? Or will it?

We would like for one of the near-term benefits of our research to answer this question, but I'm not sure how good we will be at it. Even in our genetic cases with our families where we have linkage scores, we have people with the stuttering gene who don't stutter. Some of them did as children, but even when we've found a gene in a family, it's not 100% predictable. That's just one of the unfortunate facts of life and certainly true of the genetics of stuttering. But we console ourselves that, even though genetics isn't perfect, it's one of the few ways you can get at the underlying pathophysiology—the cells and molecules—underlying this disorder. Coming from the pharmaceutical industry, I can tell you the people in the industry work at the level of cells and molecules and they need to know about those to develop pharmaceutical treatments. That's why we are interested at that level, too. It's very different approach from studies of brain imaging or the psychological aspects of stuttering.

How did you find the families you are studying? Is it difficult?

Most of these families were found with some amount of luck. In the family we are studying in Cameroon, there are 100 individuals, of whom 40 or so stutter. They were found by an online stuttering symposium. This fellow wrote in and said he was from Cameroon and his father was a chieftain with three wives and that he had 21 full and half-siblings who all stutter and did we think there was anything genetic involved? I replied, "We need to talk."

Our family in Pakistan was found through a collaborator who was actually standing in line at an office and he overheard a group of workmen nearby, one of whom had a significant stutter. He went over and struck up a conversation and the man told him, "Oh, yes, lots of people in my family stutter." Our collaborator asked if he could come and get blood from them and the fellow said, "Sure!" So in that case it was being in the right place at the right time.

What do you hope your research will accomplish?

One of the most important things our research has done is to legitimize this disorder as a fundamental underlying biological problem. I think there's a temptation among people to think of it as a psychological or social disorder and that's not really realistic and, in fact, counterproductive. We think this is a biomedical problem and just like alcoholism, for example, which has gone from being viewed as a character flaw to a medical condition, we think stuttering can follow a similar path. The ultimate goal of our work at the NIH is to help improve the health of the nation. One question we could ask sooner rather than later is whether the many types of stuttering therapies and approaches, all of which have varying success rates—some working very well for some people, but not for others—whether these different responses to treatment are due to underlying genetic differences. You couldn't ask that question until you had some genes to test.

How will your research potentially affect how speech-language pathologists treat stuttering?

Our genetic results at this point don't have an impact on the clinical work of speech-language pathologists. I certainly think it would benefit SLPs to understand a little bit of the genetics to see what direction this work might be heading. When I talk to SLPs, I sense anxiety, because SLPs don't usually have a lot of background in genetics and they worry about this research moving into the area of drugs and the treatment of stuttering becoming "medicalized" and moved to the realm of pediatricians. My personal view is that it will likely produce the same kind of relationship between SLPs and physicians that exists between orthopedic surgeons and physical therapists. I personally think that if there was ever a medical therapy for stuttering, the demand for SLPs will actually go up. Because how many pediatric neurologists know anything about stuttering? They're going to have to go to a speech-language pathologist to provide that expertise for them.

How will this research potentially affect people who stutter?

Stuttering is very enigmatic. It manifests itself only in humans when they speak and has its origins in the brain, which is not very accessible at the cellular or molecular realm in living humans. It has a number of puzzling clinical features. Even the most severe stutterers can sometimes speak fluently. The disorder has been around since humans could speak, it exists in every country, every culture, every socioeconomic level; and yet, it remains mysterious. It doesn't present a simple story or origin. It's a disorder where progress will not be fast and it will be in pieces. I think there will be lots of genes that will incrementally uncover the genetic origins of this disorder.

What are the big barriers to continuing your research?

I feel a strong need for the legitimization of the disorder. No one dies of stuttering. If you talk to people who don't stutter, they think of it as a minor annoyance. But if you talk to people who are lifelong stutterers, some say this disorder has had a huge impact on their lives. Can you imagine being a 15-year-old teenager trying to call someone up on the phone to ask them for a date? Can you imagine being a captain of industry knowing exactly what you need to say, but opening your mouth and just being unable to say it? This is a more serious disorder than people believe and I think legitimization of the disorder, even though it's coming along, still has a very long way to go.

The Personal Side

I've been a geneticist for more than 30 years, working in academia, industry, and government, where I currently direct a laboratory at the National Institute on Deafness and Other Communication Disorders (NIDCD). Over the course of my career, I've worked on a wide range of human genetic disorders, but for the past 15 years my primary research focus has been stuttering. When I began my work in this area, there was only limited evidence for any type of genetic contribution to stuttering. However, several members of my family stuttered at some point, including my twin sons. My sons are fraternal twins and their stuttering, interestingly, presented in quite different ways. While one developed classic, relatively rapid-onset developmental stuttering at age 3, the other seemed fluent until the age of 6, when he began to complain of small blocks that required circumlocution. Fortunately, both of them recovered relatively quickly and they've now been fully fluent for many years.

My interest in stuttering as a disorder came from several factors. In addition to my personal experience with the disorder in my family, it was clear that stuttering offered a challenging scientific puzzle, and little was known about its underlying causes at the time. Although there was no shortage of interesting hypotheses, good data were woefully sparse, largely because stuttering is not very amenable to many of the traditional methods used in biomedical research. Genetics presented the possibility of providing new insights into stuttering at the level of cells and molecules, and I found this opportunity compelling. It was my good luck that the administration of the NIDCD agreed with this view, and provided me with an opportunity to pursue this area of research.

At this point, I feel we've made sufficient progress to demonstrate that genetic methods can provide new insights into the causes of stuttering. However, our genetic results to date can explain only a modest fraction of stuttering, and we have much work ahead of us to identify the causes in a larger number of cases of this disorder. What's particularly exciting for me, though, is that our genetic studies have opened up stuttering to many of the traditional methods in biomedical research, including studies of biochemistry, pathology, and neuroscience. We now have myriad new ways to investigate this disorder, as well as the hope that additional gene discoveries will give us a more complete picture of the underlying causes of stuttering.